Method for the production of biperidin

ABSTRACT

The invention relates to a method for the production of biperiden by reacting an exo/endo mixture of 1-(bi-cyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone with a phenyl magnesium compound to form an isomer mixture of 1-(bi-cyclo[2.2.1]hept-5-en-2-yl)-1-phenyl-3-piperidino-1-propanol, whereby biperiden is obtained therefrom by conversion of said mixture into corresponding hydrochloride, isolation of said hydrochloride, reconversion to the free base and crystallization of said biperiden.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a Section 371 National Stage Application ofApplication No. PCT/EP02/05496 filed on May 17, 2002.

The present invention relates to a method for the production ofbiperiden.

Biperiden is a well-known central anticholinergic agent and is employedfor the treatment of Parkinson's disease (Ullmanns Enzyklopädie dertechnischen Chemie, 4th edition, volume 21, Verlag Chemie, 1982, p.627). It comprises a racemate of1-(bicyclo[2.2.1]hept-5-en-2-yl(exo,R))-1-phenyl-3-piperidino-propanol(1,S)and1-(bicyclo[2.2.1]hept-5-en-2-yl(exo,S))-1-phenyl-3-piperidinopropanol(1,R)(Ia) and represents one of four possible pairs of enantiomers (Ia-d) ofthe amino alcohol1-(bicyclo[2.2.1]hept-5-en-2-yl)-1-phenyl-3-piperidino-1-propanol (I).

DE 1 005 067 and U.S. Pat. No. 2,789,110 describe the preparation of theamino alcohol I by reacting1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II) with aphenylmagnesium halide. U.S. Pat. No. 2,789,110 additionally describesthe preparation of the propanone II starting from1-(bicyclo[2.2.1]hept-5-en-2-yl)-ethanone (III), paraformaldehyde andpiperidine hydrochloride in a Mannich reaction, and the preparation ofthe ethanone III from cyclopentadiene and methyl vinyl ketone in aDiels-Alder cycloaddition.

Neither DE 1 005 067 nor U.S. Pat. No. 2,789,110 disclose whether theamino alcohol I obtained in this way is a mixture of isomers or a pureisomer.

The precursor for preparing the propanol,1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II), canexist in two isomeric forms, as exo or as endo isomer (II-exo, II-endo),and only the exo form is able to afford biperiden in the abovementionedreaction with a phenylmagnesium halide.

The structural formulae of II-exo and of II-endo show for the sake ofsimplicity in each case only one of two possible enantiomers of the exoisomer and endo isomer, respectively. However, the designation II-exo orII-endo relates hereinafter to the pair of enantiomers of the exo orendo form.

1-(Bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III), the starting substancefor synthesizing the propanone II, may also exist both as exo and asendo isomer (III-exo, III-endo) and, correspondingly, only reaction ofthe exo isomer leads in the subsequent steps to biperiden.

The structural formulae of III-exo and of III-endo show for the sake ofsimplicity in each case only one of two possible enantiomers of the exoisomer and endo isomer, respectively. However, the designation III-exoor III-endo relates hereinafter to the pair of enantiomers of the exo orendo form.

It is not possible to infer any information about the configuration ofthe precursors III and intermediates II employed in any of theabovementioned publications.

It is known that 1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III) isobtained from the cycloaddition in an exo/endo ratio of 1:4 (e.g. R.Breslow, U. Maitra, Tetrahedron Letters, 1984, 25, 1239). Since theprior art mentioned at the outset makes no statements at all about thestereochemistry of the ethanone III, it must be assumed that theethanone III was employed in this ratio of isomers to prepare the aminoalcohol I.

The preparation of exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone(III-exo) was described in 1965 by J. G. Dinwiddie and S. P. McManus (J.Org. Chem., 1965, 30, 766). This entails exo/endo mixtures of1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III) in which the endo contentpredominates being heated in methanol in the presence of sodiummethanolate and isomerizing to mixtures with an exo content of about70%. It is possible to obtain from this by fractional distillation and,where appropriate, redistillation of the distillateexo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo) with a purity ofup to 95%.

Experiments by the applicant have shown that even on use of virtuallypure exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo), i.e. of anethanone III with an exo content of at least 95%, as starting materialit is possible to obtain pure biperiden (Ia) in only low yields, withboth the reaction of1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II) with aphenylmagnesium halide and the isolation of biperiden (Ia) from themixture of isomers of the amino alcohol I formed in this reactionproceeding with a poor yield of biperiden (Ia). Pure biperiden means abiperiden (Ia) with a purity of at least 99.0%, as is generallynecessary for pharmaceutical applications.

It is an object of the present invention to provide a method forproducing biperiden (Ia) which affords the latter in a higher yield.

It has been possible to achieve this object by a method for producingbiperiden by reacting1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II) with anexo/endo ratio of at least 2.5:1 with a phenylmagnesium compound to givea biperiden (Ia)-containing mixture of isomers of1-(bicyclo-[2.2.1]hept-5-en-2-yl)-1-phenyl-3-piperidino-1-propanol (I),characterized in that the isolation of biperiden (Ia) from the mixtureof isomers comprises the following steps:

-   a) reaction of the mixture of isomers with hydrogen chloride in a    mixture of water and a polar organic solvent of limited or infinite    miscibility with water, and isolation of the hydrochloride formed    thereby,-   b) reaction of the hydrochloride in a mixture of water and at least    one polar dialkyl ether of limited or zero miscibility with water    and having 4 to 8 C atoms with a base,-   c) separation of the two phases formed at elevated temperature,-   d) evaporation of part of the ether from the organic phase and-   e) crystallization of the biperiden by cooling.

The exo and endo isomers employed in the method of the inventioncomprise, as already described for the exo and endo ethanone III-exo andIII-endo and for the exo and endo propanone II-exo and II-endo, pairs ofenantiomers. In order to obtain biperiden (Ia), which is itself aracemate, racemic mixtures of enantiomers of the starting materials andof the intermediates are employed. However, the method of the inventioncan also be applied to pure enantiomers and to non-racemic mixtures ofenantiomers.

Reaction of the propanone II with a suitable phenylmagnesium compoundusually takes place in a suitable solvent. Suitable phenylmagnesiumcompounds are phenylmagnesium halides, for example phenylmagnesiumchloride or phenylmagnesium bromide, diphenylmagnesium andphenylmagnesium alkoxides of the general formula IV

in which R is C₁–C₄-alkyl such as methyl, ethyl, n-propyl, isopropyl orn-butyl, C₄–C₆-cycloalkyl such as cyclohexyl,C₄–C₆-cycloalkyl-C₁–C₄-alkyl such as 2-cyclohexylethyl,phenyl-C₁–C₄-alkyl such as benzyl, 2-phenylethyl or 3-phenylpropyl,substituted phenyl-C₁–C₄-alkyl such as 3,4-(methylenedioxy)benzyl,heteroaryl such as 8-quinolyl, heteroaryl-C₁–C₄-alkyl such as furfuryl,2-thienylmethyl or 2-(2-thienyl)ethyl, or benzhydryl. Diphenylmagnesiumand, in particular, the phenylmagnesium alkoxide is preferably used.

Suitable solvents for the reaction of II with the phenylmagnesiumcompound are aromatic compounds such as benzene, toluene, or xylenes,acyclic or cyclic ethers having 4 to 6 C atoms, mixtures thereof ormixtures of them with aliphatic or alicyclic hydrocarbons such asn-hexane or cyclohexane. Examples of suitable acyclic ethers are diethylether and tert-butyl methyl ether, and examples of suitable cyclicethers are tetrahydrofuran and dioxane. Diethyl ether, tetrahydrofuranor dioxane or mixtures thereof are preferably used. The solvents areusually employed anhydrous, as normal for Grignard reactions.

The phenylmagnesium alkoxide IV is prepared in a generally known manner,e.g. by reacting diphenylmagnesium with an alcohol of the generalformula ROH in which R is as defined above. Diphenyl-magnesium and thealcohol are for this purpose reacted in a molar ratio in the range from1:0.9 to 1:1.5, preferably in the range from 1:1 to 1:1.2 andparticularly preferably approximately equimolar. Diphenylmagnesium,which is usually generated in situ as described hereinafter, isordinarily introduced into one of the abovementioned solvents suitablefor Grignard reactions, and the alcohol is normally added in portionsover a period of from 5 minutes up to about one hour at a temperature offrom 0 to 80° C., preferably from 0 to 50° C. and particularlypreferably from 0 to 40° C. After the addition is complete, the mixturecan be left, or preferably stirred, in the same temperature range for 15minutes to 2 hours, preferably 15 minutes to one hour, until thereaction is complete.

The diphenylmagnesium employed in the method of the invention isproduced in a manner known per se. For example, dioxane can be added toa phenylmagnesium halide, e.g. phenylmagnesium chloride, in a suitablesolvent, thus shifting the Schlenk equilibrium to result indiphenylmagnesium and the corresponding magnesium halide-dioxanecomplex. The latter usually precipitates, but is preferably not removedfrom the solution. Suitable solvents are generally acyclic and cyclicethers preferably having 4 to 6 C atoms or mixtures thereof withaliphatic, alicyclic or aromatic hydrocarbons. Examples of suitableacyclic ethers are diethyl ether and tert-butyl methyl ether, and asuitable cyclic ether is tetrahydrofuran. The suitable aliphatic andalicyclic hydrocarbons include in particular n-hexane and cyclohexane,and examples of suitable aromatic hydrocarbons are benzene, toluene andxylenes.

Dioxane is ordinarily employed at least equimolar in relation to thephenylmagnesium halide. If diphenylmagnesium is to be used asphenylmagnesium compound, then dioxane is preferably employed in excess,for example in an excess of from 50 to 500 mol %, in particular from 100to 300 mol % and specifically of from 100 to 200 mol %. Ifdiphenylmagnesium is first to be converted into the phenylmagnesiumalkoxide, preferably dioxane and the phenylmagnesium halide are employedin a molar ratio in the range from 1:1 to 1.5:1, in particular 1:1 to1.2:1 and particularly preferably approximately equimolar.

The dioxane is added to the solution of the phenylmagnesium halideusually at a temperature in the range from −20 to 60° C., preferably inthe range from −10 to 40° C.

The mixture obtained after addition of the dioxane is normally left forfrom 15 minutes to 2 hours, preferably 20 minutes to one hour, in thetemperature range mentioned for the addition of the dioxane, before itis employed in the method of the invention.

Both the preparation of diphenylmagnesium, the reaction to give thephenylmagnesium alkoxide and the Grignard reaction of thephenylmagnesium compound with the propanone II are suitably carried outunder an inert gas atmosphere. Examples of suitable inert gases arenitrogen and the noble gases such as argon, and mixtures thereof.

In the Grignard reaction of the propanone II with the phenyl-magnesiumcompound, ordinarily the phenylmagnesium compound and the propanol IIare employed in a molar ratio in the range from 0.8:1 to 3:1, preferablyfrom 1:1 to 3:1. Where diphenylmagnesium or the phenylmagnesium alkoxideis used, the phenylmagnesium compound and the propanone II areparticularly preferably employed in a molar ratio in the range from 1:1to 2:1, in particular from 1:1 to 1.3:1.

Ordinarily, the propanone II is added to the phenylmagnesium compound inthe form of a solution in one of the abovementioned organic solventssuitable for Grignard reactions at a temperature in the range from −20°C. to the boiling point, preferably in the range from −10° to 90° C. andparticularly preferably in the range from 0° C. to 70° C. Thephenylmagnesium compound is moreover ordinarily employed in aconcentration in the range from 0.1 to 10 mol/l, preferably in the rangefrom 0.1 to 3 mol/l and particularly preferably in the range from 0.2 to2 mol/l.

The propanone II can be added in one portion or, preferably, over aperiod of from a few minutes up to several hours, e.g. 5 minutes to 5hours. The propanone II is added either in the form of a solution in oneof the abovementioned inert solvents suitable for Grignard reactions or,preferably, in pure form. When added as solution, the concentration ofthe propanone II is ordinarily from 0.1 to 20 mol/l, preferably 1 to 15mol/l. To complete the reaction, the reaction mixture is normally leftat a temperature in the range from −20° C. to the boiling point of thereaction mixture, preferably in the range from −10° C. to 90° C. andparticularly preferably in the range from 10° C. to 80° C. for from 15minutes to 5 hours, specifically 30 minutes to 2 hours, during which itis preferably stirred to improve mixing. Workup is, as usual forGrignard reactions, by aqueous extraction, e.g. by quenching thereaction mixture with water, an aqueous ammonium chloride solution or anacidic aqueous solution, with the pH of the resulting mixture in thelatter case subsequently being made alkaline, extracting the quenchedmixture, where appropriate after removal of an organic phase, with awater-immiscible solvent suitable for dissolving the product, andremoving the solvent from the extract or from the extract combined withthe organic phase. Examples of suitable solvents are aromatic compoundssuch as benzene or toluene, the abovementioned acyclic ethers, esterssuch as ethyl acetate or chlorine-containing aliphatic compounds such asdichloromethane or trichloromethane.

The crude product obtained from the reaction of the propanone II with aphenylmagnesium compound consists essentially of the four diastereomericpairs of enantiomers Ia to Id of the aminopropanol I, with the pair ofenantiomers Ia (biperiden) forming the major quantity, usually at least50%.

The biperiden (Ia) is isolated from the mixture of diastereomers bydissolving the latter with heating, preferably at a temperature of from40 to 80° C., in particular from 50 to 70° C., in a mixture of water anda polar, water-miscible organic solvent. Suitable solvents areC₁–C₃-alkanols, i.e. methanol, ethanol, n-propanol and isopropanol.Aqueous isopropanol is preferably used, particularly preferably 70 to95% isopropanol and especially 90% isopropanol. The percentage datagiven here and hereinafter in relation to the isopropanol content arebased on the volume of the isopropanol relative to the total volume ofthe water-containing solvent. HCl is added to this solution, for examplein the form of a solution of hydrogen chloride in an organic solvent,preferably in one of the C₁–C₃-alkanols mentioned, with preference inisopropanol, or in the form of hydrochloric acid. HCl is employed atleast equimolar in relation to the amino alcohol I, preferably in anexcess of from 5 to 50 mol % and particularly preferably from 5 to 20mol %. The addition preferably takes place at elevated temperature, e.g.at 40 to 80° C. and in particular at 50 to 70° C. To complete thereaction after addition is complete, the reaction mixture is left at atemperature of from 50° C. up to the boiling point of the reactionmixture for 0.5 to 3 hours, preferably while stirring. In a preferredembodiment, the reaction mixture is stirred at 55 to 65° C. for thefirst two thirds of the time and then stirred at the reflux temperaturefor one third of the time. The reaction mixture is then cooled to atemperature in the range from 0 to 30° C., where appropriate stirred inthis temperature range for up to several hours, e.g. up to 10 hours,preferably up to 5 hours, and then the hydrochloride which has formed isremoved from the solution in a conventional way.

For further purification of the hydrochloride, it is generally taken upwet or dry in water and a sufficient amount of one or more polar dialkylethers of limited or zero miscibility with water and having 4 to 8 Catoms, such as diethyl ether, tert-butyl methyl ether and especiallydiisopropyl ether, and a suitable base is added to the mixture. Suitableamounts of organic solvents are, for example, from 4 to 10 ml of solventper gram of dry hydrochloride. Water and organic solvent are preferablyemployed in a ratio in the range from 1:2 to 1:5 by volume.

Suitable bases are alkali metal and alkaline earth metal hydroxides, andalkali metal carbonates; sodium or potassium hydroxide or their aqueoussolutions are particularly preferably used, sodium hydroxide or sodiumhydroxide solution in particular are used. However, it is also possibleto use water-soluble organic bases, for example amines having aliphaticsubstituents and 2 to 8 C atoms. The base is employed at leastequimolar, preferably in excess, in particular in an excess of from 5 to15 mol % based on the hydrochloride.

The reaction with the base takes place according to the invention atelevated temperature. For this purpose, before, during or, preferably,after addition of the base the mixture is heated to a temperature in therange of 25° C. up to the boiling point of the reaction mixture,preferably in the range from 30 to 70° C., and when diisopropyl ether isused as dialkyl ether preferably in the range from 40 to 65° C., inparticular from 55 to 60° C. This generally results in two clear phaseswhich are separated at elevated temperature, i.e. above 25° C.,preferably 30–70° C., in the case where diisopropyl ether is used asdialkyl ether in the abovementioned temperature range. The organic phaseis washed with water at elevated temperature, i.e. above 25° C.,preferably 30–70° C., in the case where diisopropyl ether is used asdialkyl ether in the abovementioned temperature range, and thenconcentrated preferably under atmospheric pressure by removing thesolvent until the weight/volume ratio of the product to the solvent isin the range from 1:2 to 1:6, preferably from 1:3 to 1:4.5. When themixture is cooled to room temperature or below, but preferably not below−10° C., pure biperiden (Ia) crystallizes out and is isolated byconventional methods for isolating solids, e.g. filtering off the solidor decanting off the mother liquor.

The biperiden (Ia) obtainable by the purification of the invention isobtainable, especially on use of phenylmagnesium or the phenylmagnesiumalkoxide, in a higher yield, in a higher purity and in fewer steps thanby conventional methods. The purity is usually at least 99.0% or better.

Biperiden (Ia) can then be converted with a pharmacologically acceptableacid in a conventional manner into its acid addition salt. Examples ofsuitable acids are hydrohalic acids, in particular hydrogen chloride orhydrochloric acid, and organic mono- or dicarboxylic acids such asacetic acid, oxalic acid, maleic acid, fumaric acid, lactic acid,tartaric acid, adipic acid or benzoic acid, also phosphoric acid andsulfuric acid, and the acids mentioned in “Fortschritte derArzneimittelforschung”, volume 10, pages 224 et seq., Birkhäuser Verlag,Basle, Stuttgart, 1966. Biperiden (Ia) is normally marketed ashydrochloride.

The 1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II)employed in the Grignard reaction is obtained by reactingexo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo) in a Mannichreaction in the presence of an acid with piperidine and a formaldehydesource or with the adduct of piperidine and formaldehyde, preferably ina suitable solvent.

Hereinafter, exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo) isintended to mean an ethanone III which consists of at least 96%,preferably at least 97% and particularly preferably at least 98% of theexo isomer III-exo.

Suitable solvents are, in particular, C₁–C₄-alkanols, e.g. methanol,ethanol, n-propanol, isopropanol, sec-butanol and isobutanol.Isopropanol is preferably used. The exo ethanone (III-exo) andpiperidine are usually employed in a molar ratio in the range from 0.5:1to 1.5:1, preferably 1:1. Formaldehyde is normally present in excess, itbeing possible for the excess to be up to 100 mol % based on piperidine,in particular up to 50 mol %. Formaldehyde can in this connection beemployed either gaseous, as formalin, as trioxane or asparaformaldehyde. It is preferred to use paraformaldehyde in particularin combination with piperidinium chloride. In a preferred procedure, theexo ethanone (III-exo), piperidine hydrochloride and paraformaldehydeare reacted together in molar ratios of 1:0.9–1.2:1–1.4. The solventpreferably used in this case is a C₁–C₄-alkanol, especially isopropanol.The reaction temperature is ordinarily in the range from 10° C. to theboiling point of the mixture. Heating to reflux is preferred.

The workup takes place in a manner known per se. For this purpose,usually first the solvent is removed under reduced pressure, and theresidue is taken up in water. The aqueous solution obtained in this wayis extracted with a suitable organic solvent, i.e. with awater-immiscible, moderately polar solvent, for example an aliphaticether having 4 to 6 C atoms, such as diethyl ether, tert-butyl methylether or preferably diisopropyl ether. This extraction normally takesplace at pH≦7 and serves to remove byproducts. In particular, theinitially acidic solution is extracted and then the pH of the aqueousphase is raised by adding small amounts of base, and extraction isrepeated, with a pH of≦7 being maintained. The aqueous phase is thenpreferably made alkaline by adding base in one or more stages,preferably to pH≧7.5, in particular pH 7.5 to 9 and specifically pH 8.0to 8.5, in order to convert the1-(bicyclo-[2.2.1]-hept-5-en-2-yl)-3-piperidino-1-propanone (II), whichis still in the form of the acid addition salt, into the free amine.Bases suitable for this purpose are the usual inorganic bases such asKOH, NaOH, Na₂CO₃, K₂CO₃ and the like. The aqueous phase is thenextracted one or more times with one of the abovementionedwater-immiscible moderately polar solvents, preferably diisopropylether. To isolate the propanol II from the extract, the solvent isremoved, where appropriate under reduced pressure. For furtherpurification, the residue can be purified by a vacuum distillation undera pressure of preferably less than 10 mbar, particularly preferably lessthan 5 mbar and in particular less than 1 mbar. The resulting mixtureconsists of exo- andendo-1-(bicyclo-[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II) ina ratio of at least 2.5:1, preferably of at least 3.0:1 and inparticular of 3.5–4.0:1.

A preferred method for preparing the propanone II-exo, in particular theworkup of the product obtained in the Mannich reaction of III-exo withpiperidine and formaldehyde, is described in the parallel German patentapplication 10124449.5, the disclosure of which in this regard isincorporated herein by reference.

The exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo) used toprepare the 1-(bicyclo[2.2.1]hept-5-en-2-yl)piperidino-1-propanone (II)is obtained by a Diels-Alder cycloaddition reaction of cyclopentadieneand methyl vinyl ketone. A preferred method for preparing III, whichaffords a product with a high content of III-exo, is described in theparallel German patent application 10124450.9, the disclosure of whichis incorporated herein by reference. The cycloaddition can be carriedout in a solvent conventional for such reactions, such as diethyl ether,benzene, toluene or xylene or else without solvent. It is preferred touse no solvent. Cyclopentadiene and methyl vinyl ketone are normallyemployed in a molar ratio in the range from 3.0:1 to 0.5:1. They arepreferably reacted equimolar or with cyclopentadiene in excess, with theexcess preferably being 50 to 150 mol %.

The reaction is usually carried out at temperature in the range from 0to 60° C., preferably in the range from 20 to 40° C.

Low-boiling constituents, usually unreacted precursors, are usuallyremoved following the cycloaddition by distillation under reducedpressure, preferably under 1 to 150 mbar. The remaining mixture, whichconsists of about 20% exo- and about 80%endo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone, is reacted with an alkalimetal C₁–C₄-alcoholate. The amount of alkali metal alcoholate is usuallyfrom 0.1 to 5% by weight, preferably from 0.2 to 2% by weight, based onthe total weight of the mixture. Sodium methanolate is preferably used.The temperature necessary for isomerization of the ethanone III isusually in the range from 50 to 110° C., preferably in the range from 60to 100° C. For this purpose, the mixture is often heated under reducedpressure to reflux, preferably under a pressure of from 1 to 100 mbarand in particular under a pressure of from 5 to 50 mbar. Theseconditions are usually applied for from 10 minutes to 5 hours, inparticular 20 minutes to 3 hours and specifically 0.5 hours to 2 hours,and then fractional distillation of the resulting mixture is started,preferably distilling out the exo isomer of III. It is assumed thatremoval of the exo isomer from the equilibrium promotes isomerization ofthe endo ethanone to the exo form. The fractional distillation normallytakes place through a column under reduced pressure, preferably in therange from 1 to 100 mbar, in particular from 1 to 50 and specificallyfrom 1 to 20 mbar. The distillation temperature (distillate temperature)is preferably adjusted to from 50 to 100° C. and specifically to 50 to80° C. In this way, exo-1-(bicyclo[2.2.1]-hept-5-en-2-yl)ethanone(III-exo) is obtained in a purity which is at least 96%. Redistillationof the distillate results in the exo ethanone III-exo with a purity ofup to 100%.

The following example serves to illustrate the invention but is not tobe understood as restrictive.

EXAMPLE 1. Preparation of the Starting Material

1.1 exo-1-(Bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo)

198.3 g of cyclopentadiene were rapidly added to 210.3 g of methyl vinylketone. After the addition was complete, the solution was stirred atroom temperature for one hour and then unreacted precursor was removedby distillation at a temperature of 58° C. and a pressure of 20 mbar.The residue from evaporation, mainly consisting of a mixture of the exoand the endo form of 1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III) inthe ratio of 1:4, was heated to reflux with 5 g of sodium methanolateunder a pressure of from 10 to 20 mbar for one hour. The reactionmixture was then distilled through a column at a temperature of 75° C.and a pressure of 20 mbar. This resulted in 298.3 g (73% of theory) ofexo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo) in the form of apale yellowish oil.

1.2 1-(Bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II)

68.1 g of exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo), 60.8 gof piperidine hydrochloride and 18 g of paraformaldehyde were heated toreflux in 140 ml of isopropanol for five hours. The solvent was removedin vacuo, and the residue was taken up in 100 ml of water. The solutionwas washed three times with 50 ml of diisopropyl ether each time andthen adjusted to pH 10 with 50% strength sodium hydroxide solution.Three extractions each with 50 ml of diisopropyl ether were carried out,the three extracts were combined and the solvent was removed in a rotaryevaporator. The residue from evaporation was distilled in a Kugelrohr at75° C. under high vacuum at 0.001 mbar. The distillate obtainedcomprised 50.2 g (43% of theory) of a mixture of exo- andendo-1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II) inthe ratio 3.5:1 in the form of a colorless oil.

2. Preparation of Biperiden (Ia)

603.6 g (6.85 mol) of dioxane were added to 1 500 g of a 25% strengthsolution of phenylmagnesium chloride (375 g, 2.74 mol) intetrahydrofuran while cooling to 0° C. in an ice bath, during which awhite precipitate formed. After stirring while cooling in the ice bathfor 30 min, 320 g (1.37 mol) of the 3.5:1 mixture of the exo and endoforms of 1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II)were added while cooling in the ice bath. After the addition wascomplete, the ice bath was removed and the mixture was stirred at roomtemperature for one hour. The solution was subsequently added slowly to1 500 ml of ice-cold water and then extracted three times with 500 ml oftoluene each time. The organic phases were combined, dried over sodiumsulfate and evaporated on a rotary evaporator. The residue fromevaporation, 433.8 g of a mixture which consisted essentially of formsfrom Ia to Id of1-(bicyclo[2.2.1]hept-5-en-2-yl)-1-phenyl-3-piperidino-1-propanol (I) inthe ratio (GC) 10.4:3.4:3.0:1, was dissolved in 3 500 ml of hot 90%isopropanol, and 228 ml of a 6 molar solution of hydrogen chloride inisopropanol were added to the solution at 60° C. After the addition ofacid, the mixture was stirred at 60° C. for one hour and then at thereflux temperature for 0.5 hours. After cooling to room temperature, thecrystals which had separated out were removed and washed twice with 200ml of isopropanol each time. The moist hydrochloride obtained in thisway was stirred in 1 150 ml of diisopropyl ether and 350 ml of waterwhile 135 ml of 5M sodium hydroxide solution were added. The mixture washeated to 55° C. and then, at this temperature, the aqueous phase wasseparated off and the diisopropyl ether solution was washed twice with200 ml of water each time. 500 ml of solvent were removed from thewashed diisopropyl ether solution by distillation under atmosphericpressure. The residue from distillation was allowed to cool whilestirring. It was then cooled further to 20° C. and stirred at thistemperature for one hour, and then the crystals which had separated outwere removed, washed with 50 ml of diisopropyl ether and dried in vacuoat 50° C. 118 g of biperiden (Ia) were obtained as colorless crystals ofmelting point 112 to 114° C. (Ullmanns Enzyklopädie der techn. Chemie,4th edition, volume 21, Verlag Chemie, 1982, page 627: 112–114° C.);which is 28% of theory.

3. Preparation of Biperiden Hydrochloride

6.7 g of biperiden (Ia) were dissolved in 75 ml of isopropanol byheating to the reflux temperature. The solution was filtered hot, andthe filter was washed with 7 ml of isopropanol. 4.7 ml of 5 molarhydrochloric acid were added to the combined filtrates at 75° C. Themixture was then heated to reflux for 15 minutes. After cooling to roomtemperature, the precipitated solid was filtered off with suction,washed with 7 ml of isopropanol and dried in vacuo at 70° C. 7.3 g ofbiperiden hydrochloride were obtained in the form of colorless crystalsof melting point 278 to 280° C. (Ullmanns Enzyklopädie der techn.Chemie, 4th edition, volume 21, Verlag Chemie, 1982, page 627: 278–280°C.); which is 98% of theory.

1. A method for producing biperiden by reacting an exo/endo mixture of1-(bicyclo-[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone with anexo/endo ratio of at least 2.5:1 with a phenylmagnesium compound to givea biperiden-containing mixture of isomers of 1 -(bicyclo-[2.2.1]hept-5-en-2-yl)-1-phenyl-3-piperidino-1 -propanol, characterized inthat the isolation of biperiden from the mixture of isomers comprisesthe following steps: a) reacting the mixture of isomers with HC1 in amxture of water and a polar, water-miscible organic solvent, andisolation of the hydrochloride formed thereby, b) reacting thehydrochloride with heating in a mixture of water and at least one polardialkyl ether of limited or zero miscibility with water and having 4 to8 C atoms with a base, c) separating the two phases formed at elevatedtemperature, d) evaporating part of the ether from the organic phase ande) crystallizing of the biperiden by cooling.
 2. The method of claim 1,characterized in that aqueous isopropanol is used as the solvent mixturein step a).
 3. The method of claim 1, characterized in that the mxtureof isomers is reacted in step a) with HC1 at a temperature in the rangefrom 40 to 80° C.
 4. The method of claim 1, characterized in that thehydrocholoride is isolated in step a) at a temperature in the range from0° C. to 30° C.
 5. The method of claim 1, characterized in thatdiisopropyl ether is used as the organic solvent in step b).
 6. Themethod of claim 1, characterized in that an alkali metal or alkalineearth metal hydroxide or an alkali metal carbonate or a water-solubleorganic base is used as the base in step b).
 7. The method of claim 1,characterized in that the ether is evaporated in step d) until theweight/volume ratio of product to ether is in the range from 1:2 to 1:6.8. The method of claim 1, characterized in that a phenylmagnesiumhalide, diphenylmagnesium or a phenylmagnesium alkoxide of the generalformula IV

where R is C₁–C₄-alkyl, C₄–C₆-cycloalkyl, C₄–C₆-cyclo-alkyl-C₁–C₄-alkyl,phenyl-C₁–C₄-alkyl, substituted phenyl-C₁–C₄-alkyl, heteroaryl,heteroaryl-C₁–C₄-alkyl or benzhydryl, is used as the phenylmagnesiumcompound.
 9. The method of claim 8, characterized in thatdiphenylmagnesium or the phenylmagnesium alkoxide of the formula IV isemployed as the phenylmagnesium compound.
 10. The method of claim 9,characterized in that the phenylmagnesium alkoxide of the formula IV isprepared by reacting diphenylmagnesium with an alcohol of the generalformula ROH where R has the meanings stated in claim
 9. 11. The methodof claim 9 characterized in that diphenylmagnesium is prepared byreacting a phenylmagnesium halide with dioxane, and the magnesiumhalide-dioxane complex which is formed at the same time is not removed.